Synthesis of lepidinium salts



Patented Apr. 21, 1953 SYNTHESIS OF LEPIDINIUM SALTS- Donald W. Heseltine and Leslie G. S. Brooker, Rochester, N. Y., assignors to Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey No Drawing. Original application April 8, 1950,

Serial No. 154,882. Divided and this application June 22, 1951, Serial No. 233,114

Claims. (Cl. 260-286) This invention relates to a new process for preparing lepidinium salts and new quaternary salts obtained thereby.

It is known that lepidine bases can be prepared by reacting an aromatic primary amine hydrochloride with methyl vinyl ketone in the presence of an oxidizing agent, e. g. ferric chloride. (Campbell U. S. Patent 2,451,610, dated October 19, 1948.)

We have now found that acid addition salts of aromatic secondary amines can be condensed with methyl, vinyl ketone in the presence of an oxidizing agent to give, not a lepidine base as might be expected, but a lepidinium quaternary salt.

It is, therefore, an object of our invention to provide a new method for preparing lepidinium quaternary salts. A further object is to provide lepidinium salts, some of which have not heretofore been known. Still another object is to provide a method for preparing N-aryl quaternary salts. Other objects will become apparent from a consideration of the following description and examples.

According to our invention we provide a new process for preparing lepidinium quaternary salts which comprises reacting an acid addition salt of an aromatic secondary amine with methyl vinyl ketone in the presence of an oxidizing agent.

The aromatic secondary amines whose acid addition salts can be used in our invention comprise the N-alkylarylamines, such as N-methylaniline, N-ethylaniline, N-methyl-p-chloroaniline, N- methyl-p-toluidine, etc., the diarylamines, such as diphenylamine, p,p-ditolylamine, p,p'-dichlorodiphenylamine, etc. and heterocyclic secondary amines, such as tetrahydroquinoline, dihydroindole (indoline), carbazole, 3,4,5,6-tetrahydrocarbazole, phenothiazine (thiodiphenylamine), phenoxazine (phenazoxine), 2,3-trimethyleneindoline, etc. The acid addition salts of the N-alamines useful in practicing our invention can adkylaryl and diaryl amines useful in practicing our invention can advantageously be represented by the following general formula:

wherein R represents an alkyl group, such as methyl, ethyl, etc., or an aryl group, such as phenyl, 0-, m-, or p-tolyl, o-, m-, or p-chlorophenyl, o-, m-, or p-hydroxyphenyl, etc. (e. g. a

mono-nuclear aryl group of the benzene series), D represents the non-metallic atoms necessary to complete an aromatic nucleus, such as phenyl, o-, m-, and p-chlorophenyl, etc. (e. g. a mononuclear aryl group of the benzene series), and X represents an acid radical, e. g. chlorine, bromine, iodine, sulfate, chlorate, thiocyanate, alkylsulfate (e. g. methyl sulfate), toluenesulfonate, etc. The acid addition salts of the heterocyclic secondary vantageously be represented by the following general formula:

wherein D1 represents the non-metallic atoms necessary to complete an aromatic nucleus, such as phenyl, chlorophenyl, hydroxyphenyl, etc. nuclei -(e. g. an aromatic nucleus of the benzene series), X has the meaning given above, and Z represents the non-metallic atoms necessary to complete a heterocyclic nucleus containing from 5 to 6 atoms in the heterooyclic ring, such as tetrahydropyrrole (II represents indoline type), indole (II represents carbazole or tetrahydrocarbazole type), benzothiazine (II represents phenothiazine type), etc. nuclei. The aromatic nuclei can have substituted thereon Cl, Br, alkoxyl (e. g. methoxyl, etc.), hydroxyl, etc. groups, although, as can be seen from the above general formulas, at least one of the positions ortho to the secondary nitrogen atom in the compounds of Formula I, or peri to that of the secondary nitrogen atom in the compounds of Formula 'II, should be free of substituents.

. As oxidizing agents we can advantageously use mononuclear nitroaromatic compounds of the benzene series, such as nitrobenzene, nitrotolu: ene, etc., nitroaromatic sulfonic acids, such as m- 1 nitrobenzenesulfonic acid, etc., nitrophenols, such as oand p-nitrophenol, etc., ferric halides, such as ferric chloride, etc., arsenic pentoxide or arsenic acid, etc. Ordinary less advantageously than in the presence of the conventional oxidizing agents set out above.

Instead of employing the acid addition salt of the secondary amine as such, according to the method described above and in certain. of the following examples, the secondary amine can be suspended in an aqueous solution of an acid, and the reaction carried out in this medium. Under these conditions the acid forms an addition salt with the secondary amine, and the latter undergoes condensation with the ketone. Hydrochloric or sulfuric acids have been found to provide aqueous solutions which are excellently adapted as reaction media for the process of our invention. A condensation agent or catalyst, such as zinc chloride, etc. can be added to the reaction mixtures, if desired. The condensation agent can also serve as an oxidizing agent, or can be used with an oxidizing agent, such as ferric chloride.

The reaction can be carried out at room tem- V lA-dioxane, etc., can be employedif desired.

The process of our invention can be carried out in stepwise fashion by first condensing the aromatic secondary amine addition salt with the methyl vinyl ketone, followed by oxidation of the intermediate formed in'the presence of one of the oxidizing agents mentioned above. It has been found to be most advantageous, however, to operate the process of our invention as described in the following examples.

' Among the lepidinium quaternary salts which have not previously been described that are, obtained according to the process of our invention are those represented by the following two general wherein D1 has the value set forth above, R1 repres'entda mononuclear aromatic nucleus of the benzene series (e. g. phenyl, oand p-chlorophenyL'oand p-methoxyphenyl, etc.), Z1 representsthe non metallic atoms necessary to complete a heterocyclic nucleus containing from 5 to 6 atoms 'in the heterocyolic ring, and X has the value set forth above. Among the compounds coming within the scope of Formula IV are those represented by the following threegeneral formulasi and VII

wherein D1 and K have the values set forth above, D2 represents a carbocyclic nucleus containing from 5 to 6 atoms in the ring, and n represents a positive integer from 2 to 3.

The following examples will serve to illustrate further the manner whereby we practice our invention.

Example 1.1-phenyllepidinium iodide Diphenylamine hydrochloride (102.5 g.), o-nitrophenol (46 g.) and anhydrous zinc chloride (5 g.) were dissolved in 400 cc. absolute ethyl alcohol. The reaction mixture was heated under reflux with mechanical stirring and50 g. of methylvinyl ketone were added dropwise. over a period of two hours. Theheat-ing was continued overnight and then the alcohol was removed, and the residue extracted with two liters: of boiling water. The aqueous portion was then made just alkaline with alkali, treated with decolorizing. carbon and filtered. The filtrate was acidified with hydrochloric acid, 50 g. of sodium iodideadded'and' the solution evaporated to drynessv under reduced pressure. The dry-salts were thenextracted with two 300 cc. portions of absolute ethyl: alcohol and the alcohol extracts concentrated to cc. and chilled overnight. The quaternary salt was filtered off and recrystallized from 150 cc. of water yielding 30.5 g. (17%) of amber colored'crystals with a M. P. of-233-235 C. withdecomposition.

Anal. calcd. for C1eH141'N: I, 36.6. Found: I, 36.41.

Example .2.- 1,8-trimethylenelepidinium iodide I H2O OH:

Tetrahydroquinoline hydrochloride (6.0 g), ferric chloride (anhydrous) g.) and anhydrous zinc chloride (5 g.) were dissolved-in 300 cc. of absolute ethyl alcohol. The reaction mixture was heated under reflux with mechanical stirring and 38 g. of methylvinyl ketone were added dropwise over a period of two hours. The reaction mixture was refluxed overnight and the alcohol distilled ofi. The residue was extracted with three liters of boiling water and the watersolution made just alkaline with 40% sodium-hydroxide. Filter-eel (100g) was added, the-solution filtered, and the filtrate acidified with hydrochloric acid. Then 50 got sodium iodide were added and the aqueous solution was taken to dryness under reduced'pressure. The mixture of salts was extracted with 500 cc. ofboiling absolute ethyl alcohol, the alcohol-solution concentrated to cc., and chilled overnight. The quaternary saltwas filtered ofi; dissolved in a minimum amount of boiling water. treated acsaoau with 2 g. of decolorizing carbon, filtered and chilled. The product was filtered off and dried, yielding 22 g. (19.4%) of yellow crystals having a M. P. of 186-187 C. with decomposition.

Anal. calcd. for C'13H14IN: I, 40.8. Found: I, 41.0.

Emample 3.1,8-ethylenelepidinium iodide Indoline (60 g.) was dissolved in 180 cc. of hydrogen chloride in absolute ethyl alcohol and added to 162 g. of ferric chloride in 300 cc. of

alcohol distilled 01f on the steam bath. The

residue was extracted with three liters of boiling water, the aqueous solution filtered, treated with decolorizing carbon and made just alkaline with 40% sodium hydroxide. Filter-eel (100 g.) was stirred in, the solution filtered, made just acid with hydrochloric acid and 50 g. of sodium iodide added. The aqueous solution was then evaporated to dryness under reduced pressure and the combined salts were extracted with two 300 cc. portions of absolute ethyl alcohol. The alcoholic extracts were concentrated to 150 cc. and chilled overnight. The crystalline quaternary salt was filtered oiT and recrystallized from 100 cc. of water yielding 23.8 g. (17%) of yellowish crystals having a M. P. of 192194 C. with decomposition.

Anal. calcd. for C12H12IN: I, 42.7. Found: I, 42.6.

Example 4.1,8-o-phenylenelepidinium iodide Carbazole (84 g.) was suspended in 400 cc. of absolute ethyl alcohol and 49 g. of sulfuric acid was added dropwise with stirring. Then 23 g. of o-nitrophenol and 10 g. of anhydrous zinc chloride were added and the reaction mixture heated to reflux temperature. Methylvinyl ketone (50 g) was then added dropwise over a period of two hours and the heating continued overnight. The alcohol was removed by distillation, the residue extracted with four liters of boiling water, and the aqueous extract neutralized with sodium carbonate. The water solution was treated with decolorizing carbon, filtered, aciditied with hydrochloric acid, 20 g. of sodium iodide added, and then evaporated to dryness under reduced pressure. The dry mixed salts were extracted with 500 cc. of absolute alcohol. The alcoholic solution was concentrated to 75 cc. and the quaternary salt thrown out of solution by the addition of ether. The ether-alcohol solution was decanted and the sticky residue stirred with acetone until crystalline. The quaternary salt was filtered off and recrystallized from ethyl alcohol yielding 6.2 g. (3.6%) of yellowish powder.

Example 5.1,8-(3,4,5,6-tetrahydro-o-phenylene) lepidinium iodide 3,4,5,6-tetrahydrocarbazole (85.6 g.) was dissolved in 500 cc. of nitrobenzene in a two-liter, three-necked flask fitted with a condenser and a mechanical stirrer. Concentrated sulfuric acid (49 g.) was added dropwise, the reaction mixture was heated to the reflux temperature and 70 g. of methylvinyl ketone were added dropwise over a period of one hour. The heating and stirring were continued overnight and then the nitrobenzene was removed by steam distillation. The aqueous solution was decanted from the tar, neutralized with sodium carbonate, extracted with benzene, and finally, acidified with hydrochloric acid. The aqueous portion was then evaporated to dryness under reduced pressure and the mixed salts remaining were extracted with 500 cc. of absolute ethyl alcohol. The alcoholic solution was concentrated to ml., chilled, and filtered. The crude quaternary salt was dissolved in 100 cc. of hot water and precipitated by the addition of 10 g. of sodium iodide yielding9.5 g. (5%) of brown powder. Recrystallization from water gave yellow cubes, M. P. 268-270 C with decomposition.

Example 6.1.8-o-cyclopentylenelepidinium 1,2,3,4,3a,8b-hexahydrocyclopentindole (32 g.), onitrophenol (14 g.) and zinc chloride (2 g.) were dissolved in 200 cc. of absolute ethyl alcohol in a one-liter, three-necked flask fitted with a condenser and a mechanical stirrer. Sulfuric acid (20 g.) was added dropwise with stirring, and the reaction mixture was heated to reflux. Then freshly distilled methyl vinyl ketone (20 g.) was added dropwise over a period of one hour. The reaction mixture was heated with stirring for an additional two hours and then as much alcohol as possible was removed by distillation. The residue was extracted with one liter of boilwith hydrochloric acid and concentrated to 100 cc. The crude quaternary salt was precipitated by the additionof sodium perchlorate (20 g. in 40 cc. of Water), the solution chilled and the water decanted leaving 25 g. (41 of crude product as a heavy yellow oil. The salt, after repeated washingv 'withwater, ether and ethyl alcohol and dryingfor 48'hours over calcium chloride in a vacuum desiccator, was a yellow, friable, very hydroscopic'solid.

The 1,2,3,4,3a,8b hexahydrocyclopentindole Phenothia'zine (199' g.)' was suspended in one liter of' absolute'ethyl" alcohol and o-nitrophenol (46 g.) and anhydrous zinc chloride (5- g.) were added. Concen'trated sulfuric acid (98 g.) was added'd'ro'pwise withstirri'ng. The reaction mixture was then heated to boiling in a fivediter, three-necked flask fitted with a condenser and a mechanical stirrer and'methyl vinyl ketone (freshly distilled) 80gi) was added dropwise over a period of two hours. The reaction mixture was heated under reflux overnight and then as much alcohol aspossible. removed by distillation. The residue was stirred with several portions of ether and the ether decanted. The remaining oil was stirred with three liters of acetone to remove the excessphenothiazine. The acetone was decanted and the residue extracted with one liter of boiling .water. The aqueous extract was treated with decolorizing carbon, filtered and sodium iodide (20 g.) added and the solution chilled. The: product was filtered off, washed with acetone and recrystallized from methyl alcohol and. then from water, yielding 7.3 g. (2%) of amber crystals melting at 287-288 C. with decomposition Operating in a manner similar to that illustrated above, other lepidiniu-rn salts can beiprepared according to the process of our invention. The lepidinium; salts-prepared. according to the process of our-"invention can be used in the preparation-of other: useful materialssuch as polymethine dyes, 'asd'escribed in the application of Donald. W. Heseltine and Leslie 0-.- S. BrookerySeria-lNo; 154,883, filed on April 8, 1950.

This applicationis'adivision of our application SerialNo:154,882,:filedon April 8, 1950, now U. S. :Patent 2,578,304; issued December '11, 1951.

What we claim as. our. invention and desire secured byLettersiPatent-ofthe United States is:

1. A process .-for. preparing lepidinium quater nary salts comprising. condensing I a compound *selected' from thoserepresented by the following general formula:

The desired product was wherein R represents a member selected from the group consisting of an alkyl group and an aryl group, D represents the non-metallic atoms necessary to complete an aromatic nucleus, and X represents an acid radical, with methyl vinyl ketone in the presence of an oxidizing agent.

2. A process for preparing lepidinium quaternary salts comprising condensing a compound selected from those represented by the following general formula:

RNH-C oILHX wherein R. represents a mononuclear aryl group of the benzene series D represents the nonmetallic atoms necessary to complete a mononuclear aryl group of the benzene series, and X represents an acid radical, with methyl vinyl ketone in the presence of an oxidizing agent.

3. A process for preparing lepidinium quarternary salts comprising condensing a compound selected from those represented by the following general formula:

R-NH6'" cH;HX

wherein R represents an alkyl group'containing' from} to 2 carbon atoms, D represents the nonmetallic atoms necessary to complete a mononuclear aryl group of" the benzene series, and X represents an acid radical, with methyl vinyl ketone in the presence of anoxidizing agent.

4. A process for preparing lepidiniumqu'aternary salts comprising condensing a compound selected from those represented by the following general-formula:

R-NH-db'ilHCl wherein'R represents a mcnonuclear aryl group of the'ben'zen e series a'ri'd'Drepresents the nonmetallic atoms necessary to complete a' mononuclea'r' aryl group of the benzene series; with methyl vinylketone in the presence of an oxidizingfagen't.

DONALD W. HESELTINE. LEsLIsG. s. BROOKER.

References Cited in the'fileof' this patent UNITED STATES PATENTS Number Name Date 2,158,287 Konig May 16, 1939 2,536973 Anish s Jan. 2, 1951 FOREIGN PATENTS Number Country Date 710,748 Germany Sept. 20, 1951 

1. A PROCESS FOR PREPARING LEPIDINIUM QUATERNARY SALTS COMPRISING CONDENSING A COMPOUND SELECTED FROM THOSE REPRESENTED BY THE FOLLOWING GENERAL FORMULA: 